PV Toolkit Contents

About PV Toolkit

This Pharmacovigilance (PV) Toolkit is a collection of resources and information needed for the practice of pharmacovigilance. The main aim of its development is to ensure that PV practitioners in low- and middle-income countries get access to information on the processes and activities involved in PV from a trusted source. The Toolkit contents are endorsed by the WHO Advisory Committee on the Safety of Medicinal Products after the original text has been written and reviewed by global experts.

In addition to this website, the Toolkit is available on USB drives in a similar format to this website, for use in areas with poor internet connectivity. The Toolkit is currently available in English, and efforts are underway to have it translated into other languages, although this is dependent on availability of volunteers and/or funding. The Toolkit will be reviewed periodically to ensure that it is abreast with developments in PV.

The Toolkit Management Team is keen to have your feedback such as what you think can be added, removed or modified in order to make its use more beneficial.

Development of the PV Toolkit was supported by a generous grant from the Global Fund.

The governance framework for the toolkit and the process for adoption of content can be viewed below.

The governance framework for the toolkit and the process for adoption of content.

About PV Toolkit

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Introduction

Patient safety is the focal point for health care. Modern medicines have had a positive impact on the management and control of disease conditions. However, even with all their benefits, there is evidence to the fact that adverse reactions to medicines are very common, yet often preventable.

These reactions have been the cause of illness, disability and even death and in some countries adverse drug reactions are among the 10 leading causes of mortality.

The safety of patients and the safe use of medicines are crucial for health policy development and delivery of the best healthcare. To prevent or reduce harm to patients thereby improving public health, the safety of medicines in clinical use must be monitored and evaluated through specialised systems. This means having a well-organised pharmacovigilance system.

This Pharmacovigilance (PV) Toolkit is a package of simple PV tools and a description of supporting processes for the conduct of pharmacovigilance. It is targeted primarily at PV professionals in low and middle income countries, but is relevant everywhere PV is practised. It provides the framework and support needed for the effective conduct of pharmacovigilance at local, regional, national and international levels.

One of the essential aims of WHO and its partners is to provide countries with the necessary support and tools to be able to carry out pharmacovigilance activities effectively and in a harmonised way to ensure that data collected in each setting can be used globally. This current Toolkit is one example of this work. It aims to provide countries with a complete guide, tools and assistance to undertake comprehensive pharmacovigilance according to WHO guidelines and recommendations and in line with contemporary best practice. It also provides a means of monitoring and evaluating activities using a novel pharmacovigilance indicator that all countries can use to measure performance. This is a much neglected area and deserves more attention if PV is to become more effective and continue to be funded.

Tell us what you thinkThe Toolkit Development and Management Teams are very keen to hear from you, what you think about the Toolkit and about ways in which you think it can be improved, what is missing, what is confusing or unclear. Please email us with your frank opinions: comments@pvtoolkit.org

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Functions of National PV System

The functions of a national pharmacovigilance system are numerous and varied. Through consultation between WHO, the WHO Advisory Committee on the Safety of Medicinal Products (ACSoMP) and The Global Fund, the minimum functions of a national pharmacovigilance system have been defined to include the following:

To promote PV in the country, collect and manage ADR reports as well as reports of medication errors and suspected counterfeit/substandard drugs

To collaborate and harmonize with other ADR collection activities within the country (e.g. national disease control programmes, poison control centres, etc.) as well as international monitoring of ADRs in cohorts of defined patients

To identify signals of drug safety, i.e. unknown or poorly characterized adverse events in relation to a drug or drug combination and/or its use

To undertake assessment of risk and options for risk management

To identify if there are quality problems in medicines resulting in ADRs; and more generally, support the identification of medicine quality issues

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How to Setup a PV Center

The setting up of a national PV centre requires several considerations. The WHO and UMC have produced a manual titled: “Safety Monitoring of Medicinal Products: Guidelines for Setting Up and Running a Pharmacovigilance Centre” which contains Basic steps in setting up a Pharmacovigilance Centre, i.e.

Make contacts with the health authorities and with local, regional or national institutions and groups, working in clinical medicine, pharmacology and toxicology outlining the importance of the project and its purposes.

Design a reporting form and start collecting data by distributing it to hospital departments, family practitioners, etc.

Produce printed material to inform health professionals about definitions, aims and methods of the pharmacovigilance system.

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PV Methods

Several methods can be used to collect safety information in pharmacovigilance. In all national pharmacovigilance systems, SPONTANEOUS REPORTING forms the bedrock of the system despite its well-known limitation of under-reporting. It is relatively inexpensive and provides a life-time monitoring of all medicines in all patients in any healthcare system. There are other systems including active patient follow-up e.g. Cohort Event Monitoring (CEM). Brief highlights of the various pharmacovigilance methods are given below (adapted from the ICH E2E Guidelines. The full document can be downloaded from the ICH website using this link.

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Definitions and Terminologies

The following definitions are used in the WHO Programme for International Drug Monitoring and member countries are encouraged to utilize them. Most of these definitions have been incorporated into guidelines issued by the ICH, EMEA and other competent national authorities. Full details, comments and explanatory notes for these are available in the Glossary of Terms from the Uppsala Monitoring Centre (WHO-UMC – Public Services – Pharmacovigilance – Definitions – Glossary of Terms in Pharmacovigilance).

In spite of the above it is important to understand that there is a rapid change in the scope of pharmacovigilance and its practice. The move towards a greater patient safety focus, changes in legislation largely in the USA and the EU, and changes in databases and technology has caused some re-thinking of definitions. Some of this thinking is incorporated in the article Adverse drug reactions: definitions, diagnosis, and management[1]. Even this will be updated soon.Of course, definitions are important so that we can converse and write about pharmacovigilance with greater clarity each of us knowing what the jargon means. Change upsets this so that below in italics newer definitions are accompanied by the reasons for changes.

Pharmacovigilance

The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems[2].

In line with this general definition, underlying objectives of pharmacovigilance in accordance with the applicable EU legislation for are:

preventing harm from adverse reactions in humans arising from the use of authorised medicinal products within or outside the terms of marketing authorisation or from occupational exposure; and

promoting the safe and effective use of medicinal products, in particular through providing timely information about the safety of medicinal products to patients, healthcare professionals and the public.

Pharmacovigilance is therefore an activity contributing to the protection of patients’ and public health.[3]

Adverse reaction

“A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.[4]“

“An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.[5]”

Adverse reactions may arise from use of the product within or outside the terms of the marketing authorization or from occupational exposure. Conditions of use outside the marketing authorization include off-label use, overdose, misuse, abuse and medication errors.

This definition can include medication error which is a major cause of adverse effects due to drugs, it includes harm from counterfeit drugs, it includes accidental overdose, it includes all medicinal products (so it includes delivery systems such as inhalers), it includes quality problems and excipients. This definition therefore includes adverse effects from a much broader range of causes. On the other hand the latter part of the definition focuses on the value of knowing about adverse effects: we want to know about those we can do something about in terms of prevention, diagnosis or treatment.

‘Adverse reaction’ and ‘adverse effect’ are interchangeable but adverse effect is more patient-centred, and adverse reaction is more drug-centred.

Unexpected adverse reaction

An adverse reaction, the nature or severity of which is not consistent with domestic labeling or market authorization, or expected from characteristics of the drug.

Adverse event (AE); synonym: Adverse experience

Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment.

An adverse event can therefore be any unfavourable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Side effect

Any unintended effect of a pharmaceutical product occurring at doses normally used in man which is related to the pharmacological properties of the drug.

Signal

Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information.

This is considerably outmoded as a general definition. It retains some value in respect of signals from ‘spontaneous reports’, but it fails to include signals from published series or from examination of health care records, laboratory experiments, or from clinical trials or epidemiological studies. ‘Incompletely documented previously’ is also a statement which requires interpretation. A single definition of a Signal is very challenging, because of the different types of information that might constitute a signal in different contexts. A basic difficulty is: what is new? And to whom? Aronson and Hauben[6] considered all definitions they could find and then produced a new one:

“Information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, which would command regulatory, societal or clinical attention, and is judged to be of sufficient likelihood to justify verifiable and, when necessary, remedial actions.”

Edwards and Lindquist in, ‘First catch your signal’[7] , took a different approach giving a more descriptive view of what a signal means and some practical advice on an approach to signal management.

The latest CIOMS monograph – CIOMS VIII – recently published gives a good deal of information about current thinking on signal management. It is a lengthy document, but it has an authoritative section on data mining in the context of signal detection.

Serious adverse event or reaction

A serious adverse reaction is any untoward medical occurrence that at any dose:

results in death or

is life-threatening or

requires in-patient hospitalisation or prolongation of existing hospitalization or

results in persistent or significant disability or incapacity or

results in a congenital anomaly/birth defect.

To ensure no confusion or misunderstanding of the difference between the terms “serious” and “severe”, the following note of clarification is provided:

The term “severe” is not synonymous with serious. In the English language, “severe” is used to describe the intensity (severity) of a specific event (as in mild, moderate or severe); the event itself, however, may be of relatively minor medical significance (such as severe headache). Seriousness (not severity) which is based on patient/event outcome or action criteria serves as guide for defining regulatory reporting obligation.

Life-threatening in this context refers to a reaction in which the patient was at risk of death at the time of the reaction; it does not refer to a reaction that hypothetically might have caused death if more severe.

Medical and scientific judgement should be exercised in deciding whether other situations should be considered serious reactions, such as important medical events that might not be immediately life threatening or result in death or hospitalisation but might jeopardise the patient or might require intervention to prevent one of the other outcomes listed above. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or development of dependency or abuse

Any suspected transmission via a medicinal product of an infectious agent is also considered a serious adverse reaction.

Spontaneous report, synonym: Spontaneous notificationAn unsolicited communication by a healthcare professional or consumer to a company, regulatory authority or other organisation (e.g. the World Health Organization, a regional centre, a poison control centre) that describes one or more adverse reactions in a patient who was given one or more medicinal products and that does not derive from a study or any organised data collection scheme.

In this context, an adverse reaction refers to a suspected adverse reaction.

Stimulated reporting can occur in certain situations, such as after a direct healthcare professional communication (DHPC), a publication in the press or questioning of healthcare professionals by company representatives, and adverse reaction reports arising from these situations are considered spontaneous reports provided the report meets the definition above. Reporting can also be stimulated by invitation from patients’ or consumers’ organisations to their members. Reporting made in the context of early post-marketing phase vigilance (EPPV), e.g. in Japan, is also considered stimulated reporting.

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Signal identification General Approach

The identification of signals in the national pharmacovigilance centre’s database, or another database, of adverse events or suspected adverse reactions requires careful review of individual reports and events. Careful, informed, routine, systematic and standardized clinical review of the Centre’s reports with the recording and appropriate collation of good data provides the quickest and most satisfying way of identifying previously unsuspected adverse reactions. Following through the whole process from relationship assessment, to signal identification, to signal strengthening, to communicating the findings is essential.

It is important to stress that new pharmacovigilance systems may have very few reports and may not be able to detect signals. It is therefore important for them to follow closely what is going on in other centres and also to rely on the WHO Pharmaceuticals Newsletter and the UMC’s Signal document to keep abreast of signals that may be of importance to them. International collaboration is always key to both signal identification and signal strengthening and should be encouraged.

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Crisis Management

Every day, somewhere in the world, there are crises in healthcare: serious or fatal unexpected adverse effects of drugs; allegations about damage from vaccines; outbreaks of infections in hospitals; the emergence of resistant strains of bacteria; the discovery of sub-standard drugs; evidence of failure to prevent harm to patients, and hundreds more.

No system of regulation, no hospital, public health programme, clinic, pharmaceutical company, Ministry, department or official is immune to the risk; crises will happen and usually when you least expect them.

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Resources for PV

The section below is intended to provide support to new pharmacovigilance centres in undertaking pharmacovigilance activities. It is not intended to be all-exhaustive and would be updated in line with contemporary trends. They are guides only and further information and support may also be obtained from WHO, UMC, the WHO Collaborating Centres for Pharmacovigilance or from other national centres.

No system of regulation, no hospital, public health programme, clinic, pharmaceutical company, Ministry, department or official is immune to the risk; crises will happen and usually when you least expect them.

The Global Fund Against AIDS, Tuberculosis and Malaria (The Global Fund)Financing mechanism for the three killer diseases. The Global Fund works in a transparent way which involves all stakeholders. It is run by an international multi-stakeholder governing board.www.theglobalfund.org

The Bill & Melinda Gates Foundation (Gates Foundation)Works to help all people lead healthy, productive lives. In developing countries, it focuses on improving people’s health and giving them the chance to lift themselves out of hunger and extreme poverty.www.gatesfoundation.org

The Roll Back Malaria PartnershipThe RBM Partnership is the global framework to implement coordinated action against malaria. The website is an excellent resource for all things malaria.www.rollbackmalaria.org

WHO Collaborating Centre for International Drug Monitoring: The Uppsala Monitoring Centre (UMC)This site provides very useful information about practical pharmacovigilance including definitions and advice on pharmacovigilance policy.www.who-umc.org

WHO Collaborating Centre for Advocacy and Training in Pharmacovigilance, GhanaThe WHO-CC in Accra, Ghana works very closely with UMC and WHO and was set up to assist in particular countries in Africa. It provides training and advocacy in pharmacovigilance and distributes materials from WHO and UMC to countries who request it. The Centre is very closely aligned to the Uppsala Monitoring Centre (Africa), UMC-A, which provides access to the resources and tools of the UMC in Sweden.www.who-pvafrica.org

The WHO Collaborting Centre for Pharmacovigilance, MoroccoThe National Centre in Rabat, Morocco was appointed as a WHO Collaborating Centre for Pharmacovigilance in 2011. The Centre will conduct and facilitate regional and national pharmacovigilance training courses for Francophone, Eastern Mediterranean and Arabic countries, support the WHO normative functions related to pharmacovigilance and promote patient safety and assist WHO in the PV assessments and in the provision of technical support to Member States in pharmacovigilance and patient safety.www.capm.ma

International Society of Pharmacovigilance (ISoP)This is an important international society. Their web site gives information about meetings and training courses.www.isoponline.org

International Society for Pharmacoepidemiology (ISPE)This site is a useful source of information on the activities of the society and for guidelines on risk management and links to relevant information.www.pharmacoepi.org

International Pharmaceutical Federation (FIP)Founded in 1912, the International Pharmaceutical Federation (FIP) is the global federation of national associations of pharmacists and pharmaceutical scientists and is in official relations with the World Health Organization (WHO).www.fip.org/

Drug Information Association (DIA)DIA is a neutral, non-profit, global, professional association of nearly 18,000 members who work in every facet of the discovery, development, and life cycle management of pharmaceuticals, medical devices, and related products.www.diahome.org/DIAHome/Home.aspx

Drug Safety Research Unit (DSRU)The Drug Safety Research Unit (DSRU) is a leading independent academic research organisation internationally renowned for its work in Prescription Event Monitoring (PEM), Drug Safety and Educational Activities for more than two decades.www.dsru.org/

European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)is a project led by the European Medicines Agency and developed in collaboration with European experts in the fields of pharmacoepidemiology and pharmacovigilance. Its goal is to further strengthen the post-authorisation monitoring of medicinal products in Europe.www.encepp.eu/

The Brighton CollaborationThe Brighton Collaboration website provides information on vaccine safety and is the leading source for standardized case definitions of adverse events following immunization.www.brightoncollaboration.org

Institute for Safe Medication Practices (ISMP)The Institute for Safe Medication Practices (ISMP) is a non-profit organization devoted entirely to medication error prevention and safe medication use. The organization is known and respected worldwide as the premier resource for impartial, timely, and accurate medication safety information.www.ismp.org/

Food and Drug Administration (FDA), USAThis is a useful resource on product information, current issues and regulatory actions.www.fda.gov/

Medicines and Healthcare Products Regulatory Agency (MHRA), UKThis is a useful resource containing information and several documents targeted mainly at UK practitioners but nonetheless very useful for other countries.www.mhra.gov.uk

New Zealand Medicines and Medical Devices Safety Authority (Medsafe)This is a good resource for datasheets for medicines and patient leaflets. It also has articles in Prescriber update, many of which come from the National Pharmacovigilance Centre.www.medsafe.govt.nz/

Netherlands Pharmacovigilance Centre (Lareb)This website provides access to the database of the Netherlands Pharmacovigilance Centre as well as signals generated by Lareb. Information is available in either Dutch or English.www.lareb.nl

Council for International Organizations of Medical Sciences (CIOMS)CIOMS is an international, non-governmental, non-profit organization established jointly by WHO and UNESCO It publishes several standardized materials on pharmacovigilance. The CIOMS website also the standard “CIOMS ADR Reporting Form” that several pharmacovigilance have utilized to provide the content for designing their own ADR reporting forms.www.cioms.ch

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)ICH is a project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of pharmaceutical product registration. Detailed information on ICH guidelines and requirements are available here.www.ich.org

Rapid Pharmacovigilance Implementation in Developing Countries (RaPID)The RaPID program, a consortium of the leading organizations in pharmacovigilance, can help develop a short- and a long-term solution. The short-term solution could be implemented within 90 days, while the long-term solution, to build institutional capacity at the country level will take 3-5 years.www.rapidpharmacovigilance.org/

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Technical/Financial Assistance and Training course Providers

Several organisations are involved in providing technical assistance in pharmacovigilance to countries, donor organisations and the pharmaceutical industry. The list provided below is restricted to those organisations whose activities are aimed primarily to providing technical assistance to governments, organisations and centres in resource-limited settings and excludes those whose activities are aimed solely at the pharmaceutical industry. They are divided into Collaborating Centres, Financing Entities, Technical Agencies, Academic/Research Institutions and Consultants though the distinctions may be arbitrary in that some financing entities may directly or indirectly also provide technical assistance.

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Monitoring and Evaluation

There is a need for a globally acceptable monitoring and evaluation format for pharmacovigilance including pharmacovigilance indicators to permit all stakeholders to be able to assess the capacity, functioning and progress of any pharmacovigilance system. The World Health Organization through its Advisory Committee on the Safety of Medicinal Products (ACSoMP) has been developing a new set of Pharmacovigilance Indicators as part of its normative work. The final version is being discussed with various stakeholders and would be publicly available in the first half of 2012.

A comprehensive Indicator-based Pharmacovigilance Assessment Tool (IPAT) has been produced by the USAID-supported Strengthening Pharmaceutical Systems Programme implemented by Management Sciences for Health, USA. The full document can be downloaded using this link.

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QUICK CONTACT

ONE VigilancePLACE
Mango Tree Avenue
Asylum Down
Accra - Ghana

Phone: +233-302-268-746 / +233-289-014-000
Fax: +233-302-268-746

ABOUT THE TOOLKIT

This Pharmacovigilance (PV) Toolkit is a collection of resources and information needed for the practice of pharmacovigilance. The main aim of its development is to ensure that PV practitioners in low- and middle-income countries get access to information on the processes and activities involved in PV from a trusted source.